Outcomes of a Geriatric Liaison Intervention to Prevent the Development of Postoperative Delirium in Frail Elderly Cancer Patients: Report on a Multicentre,Randomized, Controlled Trial

Background

Delirium is a serious and common postoperative complication, especially in frail elderly patients. The aim of this study was to evaluate the effect of a geriatric liaison intervention in comparison with standard care on the incidence of postoperative delirium in frail elderly cancer patients treated with an elective surgical procedure for a solid tumour.

Methods

Patients over 65 years of age who were undergoing elective surgery for a solid tumour were recruited to a multicentre, prospective, randomized, controlled trial. The patients were randomized to standard treatment versus a geriatric liaison intervention. The intervention consisted of a preoperative geriatric consultation, an individual treatment plan targeted at risk factors for delirium, daily visits by a geriatric nurse during the hospital stay and advice on managing any problems encountered. The primary outcome was the incidence of postoperative delirium. The secondary outcome measures were the severity of delirium, length of hospital stay, complications, mortality, care dependency, quality of life, return to an independent preoperative living situation and additional care at home.

Results

In total, the data of 260 patients were analysed. Delirium occurred in 31 patients (11.9%), and there was no significant difference between the incidence of delirium in the intervention group and the usual-care group (9.4% vs. 14.3%, OR: 0.63, 95% CI: 0.29–1.35).

Conclusions

Within this study, a geriatric liaison intervention based on frailty for the prevention of postoperative delirium in frail elderly cancer patients undergoing elective surgery for a solid tumour has not proven to be effective.

Trial Registration

Nederlands Trial Register Trial ID NTR 823     

Understanding the Molecular Determinants Driving the Immunological Specificity of the Protective Pilus 2a Backbone Protein of Group B Streptococcus

The pilus 2a backbone protein (BP-2a) is one of the most structurally and functionally characterized components of a potential vaccine formulation against Group B Streptococcus. It is characterized by six main immunologically distinct allelic variants, each inducing variant-specific protection. To investigate the molecular determinants driving the variant immunogenic specificity of BP-2a, in terms of single residue contributions, we generated six monoclonal antibodies against a specific protein variant based on their capability to recognize the polymerized pili structure on the bacterial surface. Three mAbs were also able to induce complement-dependent opsonophagocytosis killing of live GBS and target the same linear epitope present in the structurally defined and immunodominant domain D3 of the protein. Molecular docking between the modelled scFv antibody sequences and the BP-2a crystal structure revealed the potential role at the binding interface of some non-conserved antigen residues. Mutagenesis analysis confirmed the necessity of a perfect balance between charges, size and polarity at the binding interface to obtain specific binding of mAbs to the protein antigen for a neutralizing response.     

Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer

Emerging evidence suggests that metformin, a widely used anti-diabetic drug, may be useful in the prevention and treatment of different cancers. In the present study, we demonstrate that metformin directly inhibits the enzymatic function of hexokinase (HK) I and II in a cell line of triple-negative breast cancer (MDA-MB-231). The inhibition is selective for these isoforms, as documented by experiments with purified HK I and II as well as with cell lysates. Measurements of ¹⁸F-fluoro-deoxyglycose uptake document that it is dose- and time-dependent and powerful enough to virtually abolish glucose consumption despite unchanged availability of membrane glucose transporters. The profound energetic imbalance activates phosphorylation and is subsequently followed by cell death. More importantly, the “in vivo” relevance of this effect is confirmed by studies of orthotopic xenografts of MDA-MB-231 cells in athymic (nu/nu) mice. Administration of high drug doses after tumor development caused an evident tumor necrosis in a time as short as 48 h. On the other hand, 1 mo metformin treatment markedly reduced cancer glucose consumption and growth. Taken together, our results strongly suggest that HK inhibition contributes to metformin therapeutic and preventive potential in breast cancer.     

Morphological differences between violets growing at heavy metal polluted and non-polluted sites

Environmental conditions, especially pollution of soils by heavy metals, can severely affect plant morphology, anatomy and reproduction. In present investigation, the morphological variability of forest violets (Viola reichenbachiana and V. riviniana), their degree of colonization by arbuscular mycorrhizal fungi (AMF) and their reproduction properties were studied using samples from ore-bearing areas with soils rich in heavy metals. In these habitats, individuals with typical morphological characters of V. reichenbachiana and V. riviniana were not identified but populations were intermediate between these two species. Three ore-bearing areas with soils of a high content but low extractable amounts of heavy metals (Pb, Zn, Cd) were covered by anthropogenic pine or beech forests, contrary to typical calamine heaps with metallophyte floras. Violets growing on ore-bearing areas were fully fertile, deposited Pb and Zn mainly in roots and had low Cd levels both in shoots and roots. Plants differed in AMF colonization with the degrees varying from nil to moderate. The violets growing in these areas were not affected in their reproduction and can be considered as stabilized introgressive forms or ecotypes of parental species on these soil conditions.     

Walnut diet reduces accumulation of polyubiquitinated proteins and inflammation in the brain of aged rats

An increase in the aggregation of misfolded/damaged polyubiquitinated proteins has been the hallmark of many age-related neurodegenerative diseases. The accumulation of these potentially toxic proteins in brain increases with age, in part due to increased oxidative and inflammatory stresses. Walnuts, rich in omega fatty acids, have been shown to improve memory, cognition and neuronal effects related to oxidative stress (OS) and inflammation (INF) in animals and human trials. The current study found that feeding 19-month-old rats with a 6% or 9% walnut diet significantly reduced the aggregation of polyubiquitinated proteins and activated autophagy, a neuronal housekeeping function, in the striatum and hippocampus. Walnut-fed animals exhibited up-regulation of autophagy through inhibiting phosphorylation of mTOR, up-regulating ATG7 and Beclin 1, and turnover of MAP1BLC3 proteins. The clearance of polyubiquitinated protein aggregates such as p62/SQSTM1 was more profound in hippocampus, a critical region in the brain involved in memory and cognitive performance, than striatum. The clearance of ubiquitinated aggregates was in tandem with significant reductions in OS/INF, as indicated by the levels of P38-MAP kinase and phosphorylations of nuclear factor kappa B and cyclic AMP response element binding protein. The results demonstrate the effectiveness of a walnut-supplemented diet in activating the autophagy function in brain beyond its traditionally known antioxidant and anti-inflammatory benefits.     

Antimicrobial enzymes: An emerging strategy to fight microbes and microbial biofilms

With the increasing prevalence of antibiotic resistance, antimicrobial enzymes aimed at the disruption of bacterial cellular machinery and biofilm formation are under intense investigation. Several enzyme-based products have already been commercialized for application in the healthcare, food and biomedical industries. Successful removal of complex biofilms requires the use of multi-enzyme formulations that contain enzymes capable of degrading microbial DNA, polysaccharides, proteins and quorum-sensing molecules. The inclusion of anti-quorum sensing enzymes prevents biofilm reformation. The development of effective complex enzyme formulations is urgently needed to deal with the problems associated with biofilm formation in manufacturing, environmental protection and healthcare settings. Nevertheless, advances in synthetic biology, enzyme engineering and whole DNA-Sequencing technologies show great potential to facilitate the development of more effective antimicrobial and anti-biofilm enzymes.     

Structure-activity relationships in corpora allata of the cockroach Diploptera punctata: roles of mating and the ovary

Morphometric studies were made on corpora allata of the cockroach Diploptera punctata from animals in which increasing gland size is not coupled to hormone synthesis (ovariectomized mated females; last-instar larvae) and in which gland size is coupled to hormone synthesis (normal mated and virgin females; penultimate-instar larvae). Cell number, gland volume, and juvenile hormone synthesis were measured. From electron micrographs, nuclear, cytoplasmic, and extracellular volumes; and cell membrane area were calculated; and fine structure described. Low-activity glands of ovariectomized mated females resembled high-activity glands from mated females in high cell number, large overall and cytoplasmic volume, and low nuclear-cytoplasmic ratio; they differed in having organelles typical of low-activity glands, mitochondria with dense matrices and large whorls of smooth endoplasmic reticulum. Inactive lastinstar larval glands resembled mated ovariectomized, female glands in increased cell number and organelles characteristic of inactive glands; however, their nuclearcytoplasmic volume ratio was much higher. Penultimate cytoplasmic volume ratio was much higher. Penultimate larval glands with high activity per cell resembled active glands of normal mated females. Ovariectomy did not change morphometric parameters of virgin female glands; thus mating results in increase in size of adult female glands whereas the growing ovary is needed for changes in mitochondria and endoplasmic reticulum associated with high juvenile hormone synthesis.     

Synthesis physicochemical profile and PAMPA study of new NO-donor edaravone co-drugs

A new class of co-drugs were synthesised by joining antioxidant edaravone with a vasodilating substructure containing NO-donor nitrooxy functions, and characterised for their stability in different media, lipophilicity and permeability profile. The products display good stability in water/co-solvent at different pH. Conversely, they are rapidly metabolised into edaravone and NO-donor moieties when incubated in human serum or rat-liver homogenates. In the latter conditions time dependent production of nitrite/nitrate (NO(x)) occurs. The compounds display wide-ranging lipophilicity. PAMPA studies predict good gastrointestinal absorption for a number of these compounds. The title products are potentially useful for treating ROS-related conditions accompanied by decreased NO availability.     

c-Jun N-terminal kinase upregulation as a key event in the proapoptotic interaction between transforming growth factor-beta1 and 4-hydroxynonenal in colon mucosa

Cells of colonic mucosa are sensitive to the Smad-mediated growth-inhibitory effect of transforming growth factor-beta1 (TGF-beta1). Another important cell growth inhibitor is the polyunsaturated lipid peroxidation end product, 4-hydroxynonenal (HNE), which triggers apoptosis through c-Jun N-terminal kinase (JNK) activation. Interestingly, a close association between TGF-beta1 and HNE was found in the progression of human colon cancer, with concentration of both molecules inversely related to the malignancy. We investigated the cross talk between Smads and JNK signal transduction pathways in inducing apoptosis. To this purpose TGF-beta1 and HNE were added singly or in combination to CaCo-2 human colon adenocarcinoma cells. The cotreatment induced a marked enhancement of apoptosis and of JNK and Smad4 activities much more than either individual molecule. Cell preincubation with the JNK inhibitor SP600125 significantly prevented JNK and Smad4 enhancement and, subsequently, the cooperative proapoptotic effect was abolished. The primary role of JNK activity in TGF-beta1/HNE cooperative signaling was fully confirmed in a second set of experiments by using JNKi I, a more selective kinase inhibitor. Hence, in tumor cells becoming resistant to TGF-beta1-mediated growth inhibition, increased induction of the remaining TGF-beta1 pathways by interaction with other antiproliferative molecules, such as HNE, could help in inhibiting tumor growth.